Pima Indians have the highest known prevalence of NIDDM, and previous studies indicated that genetic factors contribute to this predisposition. We have initiated a systematic search for NIDDM gene(s) by sib-pair linkage analysis of microsatellite markers covering all autosomes and the X chromosome. During the first phase of this project (aimed to type markers initially at a 20cM average distance), we have detected possible linkage of NIDDM with D7S479 on 7q21.3-q22.1. We have expanded this observation by analyses of 13 additional markers, most of them clustered within 25cM around D7S479. We have found indication of a possible linkage with NIDDM also for D7S527, D7S491, and D7S518, which are all within less than 6cM from D7S479. We conclude that our linkage data are consistent with the location of a putative NIDDM locus near D7S479. Several loci were mapped previously to this segment of 7q, and the physical position of D7S527, D7S479, D7S491, D7S518, and of the cloned genes within 7q21-q22 has already been determined by YAC contig analysis. We are considering three genes as potential candidates. These include TAC2 (encoding a precursor of several neuropeptides of the tachykinin family), GNB2 (encoding beta-2 subunit of GTP-binding regulatory proteins), and ACHE (encoding acetylcholine esterase) because they are located within physical proximity to D7S479 (approximately 3 mb), and could affect control of glucose homeostasis.